University of Khartoum Graduate College
Medical & Health Studies Board
Histopathological Patterns of Conjunctival Masses in Sudanese Patients
By
Hagir Hussein Taha Ahmed
M.B.B.S. ELzaeim ELazhri University 2002
A thesis submitted in partial fulfillment for the requirements of the degree of Clinical MD in Pathology
Supervisor:
Dr. Ahmed Ebrahim Shumo M.B.B.S (U of K)
Diploma of Clinical Pathology( University of London)
Chapter one
Introduction
and
Literature Review
Chapter Three
Results
References
Questionnaire Conjunctival Biopsy Name:……… Age:………. Sex:……….. Lab No:………. Date……… Refer Hospital:……….…………. Tel NO:……….……….. Specimen:………..……….……..… ………..……… ………..……… Clinical information: ………..……… ………..……… Macroscopy: ……….……… ………..………… ……….……… Microscopy: ……….……… ……… ………..……… Immune histochemistry: ………..……… ………..……… ………..……… Diagnosis: ………..… ………..……… ………..………
List of Contents Dedication I Acknowledgement II Abbreviations III English Abstract IV Arabic Abstract VI
List of tables VIII
List of figures X
Chapter One: Introduction and Literature Review 1
1.1 Development of eye 2
1.2 Histology and Anatomy 2
1.3 Developmental anomaly of eye 4
1.4 Inflammation of conjunctiva 5
1.5 Tumours of the conjunctiva 7
Objectives 36
Chapter two: Methodology 37
Chapter Three: Results 38
Chapter Four: 4.1 Discussion 69 4.2 Conclusions 73 4.3 Recommendations 74 References 75 Appendices
To the spirit of my father
To my mother
To my husband and my kids
To the members of my family with
great appreciation
I would like to express my deepest thanks to my supervisors Prof: A.E Shumo and Dr. Mohammed Mohammed Osman to their patience and continuous guidance and limitless cooperation through out of this study. I wish to thank the head of department of histopathology at national health laboratory (NHL) for making the records available for this study, Iam also grateful to the members of my family for indispensible support and encouragement that enable me to carry out this work.
I wish to thank my husband Dr. Mohammed sayed Alhassan for his help, guidance and social support.
I would also like to thank the staff at statistic unit in (N HL) for their help to get the patients records and histopathological slides.
I wish to thank Mrs. Niserin who performed the statistical analysis, together with Miss. Eynas who helped typing and printing out this work.
Abbreviations
C.T: Connective tissue SP: Substantia propria HPV: Human Papilloma virus
HBID: Hereditary benign intraepithelial Dyskeratosis. CIN: Conjunctival intraepithelial neoplasia.
PCNA: Proliferating cell nuclear Antigen P53: Tumor suppressor gene.
SCC: Squamous cell carcinoma. MEC: Mucoepidermoid carcinoma PAM: Primary Acquired Melanosis FHC: Fibrous histocytoma
HAART: Hyperactive antiretroviral therapy. KS: Kaposi’s sarcoma
EMZL: Extra nodal marginal zone lymphoma. MALT: Mucosa- associated lymphoid tissue. AIDS: Acquired immune deficiency syndrome EMA: Epithelial membrane antigen
Abstract
Objectives: The conjunctival lesions are the commonest among eye diseases. They
include a variety of pathological lesions, developmental anomalies, inflammatory , and neoplastic lesions.We aim to study patients with conjunctival masses to determine the different histopathological patterns regarding the site, frequency, age and sex incidence in Sudan.
Methods: This descriptive retrospective study was carried at the histopathology
department in the National Health Laboratory in Khartoum. The patients’data were collected during the period January 2007-December2009 from the patients’ request forms with detailed personal history, site, size and duration of conjunctival masses. Conjunctival biopsies were fixed in formalin, representative pieces of tissues were selected by a pathologist, processed by an automatic processor and then embedded in paraffin wax in form of blocks. Sections were cut in rotary microtome. Slides were prepared and stained by routine haemotoxyline-eosin stain, and re-examined by an experienced histopathologist. The data were analyzed using Statistical Package for Social Sciences Software.
Results: The study included 130 patients, their age ranged from 1 to 77 years. The
most common affected age group was between 20-40years (42%).The mean age was 35 years , with 83 males (64%) and 47female (36%).The most common affected side was the right conjunctiva. Seventy six were neoplastic lesions (58%) and fifty four were non neoplastic (42%). The most common benign lesion was pyogenic granuloma (lobular capillary haemangioma) in 32 patients (42%),it predominantly affected male children 8 (25%) . The second component of neoplastic lesions were conjunctival intraepithelial neoplasia (CIN) 26 (34%). Malignant lesions in this study were 18 cases ( 24%) , Squamous cell carcinoma was predominant (n=14) (77%). The non-neoplastic lesions were 54 cases (42%) with degenerative changes being the most common( n= 33) (61%).The inflammatory lesions constituted (n=21) (39%).
Conclusion: Conjunctival lesions are more common in males in the 3rd and 4th decades of life, mainly in the right conjunctiva. Neoplastic lesions out-numbered the non-neoplastic lesions. The degenerative changes being the commonest lesions. Squamous cell carcinoma is the most predominant malignant conjunctival lesions,which occurred mainly in males above 50 years of age.
ﺺﻠﺨﺘﺴﻤﻟا
ﻑﺍﺩﻫﻻﺍ : ﻠﻤﻟﺍ ﺕﺎﺒﺎﺼﺇ ﹰﺎﻋﻭﻴﺸ ﺭﺜﻜﻷﺍ ﻲﻫ ﺔﻤﺤﺘ ﻥﻴﺒ ﺽﺍﺭﻤﺍ ،ﻥﻴﻌﻟﺍ ﺕﺎﺒﺎﺼﺇ ﺓﺩﻋ ﻥﻤ ﻥﻭﻜﺘﺘ ﺔﻴﻀﺭﻤ ﺎﺒﺎﺼﺇ ،ﺔﻴﻘﻠﺨ ﺕﺎﻫﻭﺸﺘ ، ﺔﻴﻤﺭﻭ ﻭ ﺔﻴﺠﻤﺨ ﺕ . ﻡﺍﺭﻭﺃ ﺕﻻﺎﺤ ﺔﺴﺍﺭﺩ ﻰﻟﺇ ﺔﺴﺍﺭﺩﻟﺍ ﺕﻓﺩﻫ ﻤﻟﺍ ﺔﻤﺤﺘﻠ ﻭ ﺒ ﻕﻠﻌﺘﻴ ﺎﻤﻴﻓ ﻲﻀﺭﻤﻟﺍ ﻲﺠﻴﺴﻨﻟﺍ ﻁﻤﻨﻟﺍ ﺩﻴﺩﺤﺘ ،ﺔﺒﺎﺼﻹﺍ ﻊﻗﻭﻤ ﺱﻨﺠﻟﺍ ،ﺭﻤﻌﻟﺍ ﻭ ﺔﺒﺴﻨ ﺙﻭﺩﺤ ﺽﺭﻤﻟﺍ ﻥﺍﺩﻭﺴﻟﺍ ﻲﻓ . ﺙﺤﺒﻟﺍ ﺔﻴﺠﻬﻨﻤ : ﻫ ﺎﻫﺅﺍﺭﺠﺇ ﻡﺘ ﺔﻴﻌﺠﺭﻤ ﺔﻴﻔﺼﻭ ﺔﺴﺍﺭﺩ ﻩﺫ ﻀﻴﺭﻤﻟﺍ ﺔﺴﻨﻷﺍ ﻡﺴﻗ ﻲﻓ لﻤﻌﻤﻟﺎﺒ ﺔ ﺭﻴﺎﻨﻴ ﻥﻴﺒ ﺎﻤ ﺓﺭﺘﻔﻟﺍ ﻲﻓ ﻰﻀﺭﻤﻟﺍ ﺕﺎﻤﻭﻠﻌﻤ ﻊﻤﺠ ﻡﺘ ﺩﻗﻭ،ﻡﻭﻁﺭﺨﻟﺎﺒ ﻲﻤﻭﻘﻟﺍ ﻲﺤﺼﻟﺍ 2007 -ﺭﺒﻤﺴﻴﺩ 2009 ﻊﻗﻭﻤ ﺽﻴﺭﻤﻠﻟ ﻲﺼﺨﺸﻟﺍ ﺦﻴﺭﺎﺘﻟﺍ ﺕﻠﻤﺸ ﺙﻴﺤ ﻲﻀﺭﻤﻟﺍ ﺕﺎﻨﺎﻴﺒ ﺓﺭﺎﻤﺘﺴﺍ ﻥﻤ ﻭ ﻡﺠﺤﻭ ﻟﺍ ﺓﺩﻤ ﺕﺎﺒﺎﺼﻻ ﺔﻴﻨﻤﺯﻟﺍ ﺍ ﺔﻤﺤﺘﻠﻤﻟ . ﻰﻠﻋ ﺕﻴﺒﺜﺘﻟﺎﺒ ﺔﻠﺼﺄﺘﺴﻤﻟﺍ ﺕﺎﻨﻴﻌﻟﺍ ﺔﺠﻟﺎﻌﻤ ﺕﻤﺘ ﺯﺎﻬﺠﺒ ﺕﺠﻟﻭﻋﻭ ،ﺽﺍﺭﻤﻷﺍ ﻡﻠﻋ ﻲﺌﺎﺼﺨﺃ ﺔﻁﺴﺍﻭﺒ ﺎﻬﻨﻤ ﺕﺎﻨﻴﻋ ﺭﺎﻴﺘﺨﺍ ﻡﺘ ﻡﺜ ﻥﻤ ،ﻥﻴﻟﺎﻤﺭﻭﻔﻟﺍ ﺏﻟﺍﻭﻗ لﻜﺸ ﻲﻓ ﻥﻴﻓﺍﺭﺒﻟﺍ ﻊﻤﺸ ﻰﻠﻋ ﺕﻌﻀﻭ ﻙﻟﺫ ﺩﻌﺒﻭ ﻲﻟﻵﺍ ﺔﺠﻟﺎﻌﻤﻟﺍ . ﺔﻁﺴﺍﻭﺒ ﻊﻁﺎﻘﻤ ﻊﻁﻗ ﻡﺘ ﻱﺭﺌﺍﺩﻟﺍ ﻊﻁﺎﻘﻟﺍ . ﺍﺩﻋﺇ ﻡﺘ ﻴﺘﻭﺭﻟﺍ ﻥﻴﺴﻭﻴﻹﺍﻭ ﻥﻴﻠﻴﺴﻜﻭﺘﻭﻤﻴﻬﻟﺍ ﺔﻐﺒﺼﺒ ﺢﺌﺍﺭﺸﻟﺍ ﻎﺒﺼﻭ ﺩ ﺔﻴﻨ . ﻡﺘﻭ ﺭﺎﺒﺘﺨﺍ ﺓﺩﺎﻋﺇ ﺎﻫ ﺭﻴﺒﺨ ﺽﺍﺭﻤﺃ ﻲﺌﺎﺼﺨﺃ ﺔﻁﺴﺍﻭﺒ . لﺎﻤﻌﺘﺴﺎﺒ ﺔﻠﺼﺤﺘﻤﻟﺍ ﺕﺎﻨﺎﻴﺒﻟﺍ ﺔﺠﻟﺎﻌﻤ ﺕﻤﺘ ﺔﻴﻋﺎﻤﺘﺠﻻﺍ ﺕﺎﺴﺍﺭﺩﻠﻟ ﺔﻴﺌﺎﺼﺤﻹﺍ ﺔﻤﺯﺤﻟﺍ ﺞﻤﺎﻨﺭﺒ . ﺞﺌﺎﺘﻨﻟﺍ : ﺔﺴﺍﺭﺩﻟﺍ ﺕﻠﻤﺸ 130 ﺔﻟﺎﺤ ﺎﻤﻋﺃ ﺕﺤﻭﺍﺭﺘ ﻰﻟﺇ ﺓﺩﺤﺍﻭ ﺔﻨﺴ ﻥﻴﺒ ﺎﻤ ﻡﻫﺭ 77 ﺔﻨﺴ . ﺔﺌﻔﻟﺍ ﺕﻨﺎﻜ ﹰﺎﻋﻭﻴﺸ ﺭﺜﻜﻷﺍ ﺔﻴﺭﻤﻌﻟﺍ ﻥﻴﺒ ﺎﻤ ﻊﻘﺘ ﻡﻫﺭﺎﻤﻋﺍ 20 -40 ﺔﻨﺴ ﻤﻋﻷﺍ ﻁﺴﻭﺘﻤﻭ ، ﻥﺎﻜ ﺭﺎ 35 ﺍ ﻊﻤ ﺔﻨﺴ ﺭﻭﻜﺫﻟ 83 ) 64 (% ﺙﺎﻨﻹﺍ لﺒﺎﻘﻤ 47 ) 36 .(% ﺍ ﻊﻗﺍﻭﻤ ﺭﺜﻜﺃ ﻲﻓ ﺕﻨﺎﻜ ﺕﺎﺒﺎﺼﻹ ﻰﻨﻤﻴﻟﺍ ﺔﻤﺤﺘﻠﻤﻟﺍ . ﺔﻴﻤﺭﻭ ﺕﺎﺒﺎﺼﺍ ﻥﻭﻌﺒﺴﻭ ﺔﺘﺴ ) 58 (% ﻭ ﺔﻴﻤﺭﻭ ﺭﻴﻏ ﻥﻭﺴﻤﺨﻭ ﺔﻌﺒﺭﺍ ) 42 .(% ﻭ ﻁﺴ ﺕﺎﺒﺎﺼﺇ ﺓﺩﻴﻤﺤﻟﺍ ﻡﺍﺭﻭﻷﺍ ﻥﺎﻜ ﺔﻴﻋﻭﻷﺍ ﻡﺭﻭ ﺩﻴﻤﺤﻟﺍ ﺔﻴﻭﻤﺩﻟﺍ ) ﻲﺤﻴﻘﻟﺍ ﻲﺒﻴﺒﺤﻟﺍ ( ﺎﻋﻭﻴﺸ ﺭﺜﻜﻻﺍ ﻭﻫ " ﻲﻓ 32 ﺎﻀﻴﺭﻤ )" 42 % ( ﺭﻭﻜﺫﻟﺍ لﺎﻔﻁﻻﺍ ﻲﻓ ﺏﻠﻏ ﺩﻗﻭ، 8 ) 25 .(% ﻥﻭﻜﻤﻟﺍ ﻱﺭﺎﻬﻅﻟﺍ لﺨﺍﺩ ﺔﻤﺤﺘﻠﻤﻟﺍ ﺕﺎﺒﺎﺼﺇ ﻭﻫ ﺔﻴﻤﺭﻭﻟﺍ ﺔﻤﺤﺘﻠﻤﻟﺍ ﺕﺎﺒﺎﺼﺇ ﻥﻤ ﻲﻨﺎﺜﻟﺍ 26 ) 34 . (% ﻲﻓ ﺔﺜﻴﺒﺨﻟﺍ ﻡﺍﺭﻭﻷﺍ ﺕﺎﺒﺎﺼﺇ ﺍﺭﺩﻟﺍ ﻩﺫﻫ ﺕﻨﺎﻜ ﺔﺴ 18 ﺔﻟﺎﺤ ) 24 (% ﺔﻴﻓﺩﺼﻟﺍ ﺎﻴﻼﺨﻟﺍ ﻥﺎﻁﺭﺴ ، 14 ﺔﻟﺎﺤ ) 77 . (% ﻨﺎﻜ ﺔﻴﻤﺭﻭ ﺭﻴﻐﻟﺍ ﺕﺎﺒﺎﺼﻹﺍ ﺕ 54 ﺔﻟﺎﺤ ) 42 (% ﻤ ﻭ، ﺎﻬﻨ ﻟﺍ ﺕﺍﺭﻴﻴﻐﺘ ﻟﺍ ﺔﻴﺴﻜﻨﺘ ﻰﺘﻟﺍ ﻜﻷﺍ ﺕﻨﺎﻜ ﺭﺜ ﹰﺎﻋﻭﻴﺸ 33 ﺔﻟﺎﺤ ) 61 (% . ﻟﺍ ﺕﺎﺒﺎﺼﻹﺍ ﺕﻠﺜﻤ ﺔﻴﺠﻤﺨ 21 ) 39 (% . ﺔﺼﻼﺨﻟﺍ : ﻯﺩﻟ ﹰﺎﺜﻭﺩﺤ ﺭﺜﻜﺃ ﺕﻨﺎﻜ ﺔﻤﺤﺘﻠﻤﻟﺍ ﺕﺎﺒﺎﺼﺇ ﻊﺒﺍﺭﻟﺍ ﺩﻘﻌﻟﺍﻭ ﺙﻟﺎﺜﻟﺍ ﺩﻘﻌﻟﺍ لﻼﺨ ﺭﻭﻜﺫﻟﺍ ﻥﻤ ،ﺭﻤﻌﻟﺍ ﻰﻨﻤﻴﻟﺍ ﺔﻤﺤﺘﻠﻤﻟﺍ ﻲﻓ ﺕﻨﺎﻜ ﺔﻤﺎﻋ ﺓﺭﻭﺼﺒﻭ . ﻥﻤ ﹰﺍﺩﺩﻋ ﺭﺜﻜﺃ ﺕﻨﺎﻜ ﺔﻴﻤﺭﻭﻟﺍ ﺕﺎﺒﺎﺼﻹﺍ ﺔﻴﻤﺭﻭﻟﺍ ﺭﻴﻏ ﺕﺎﺒﺎﺼﻹﺍ . ﹰﺎﺜﻭﺩﺤ ﺕﺎﺒﺎﺼﻹﺍ ﺭﺜﻜﺃ ﺕﻨﺎﻜ ﺔﻴﺴﻜﻨﺘﻟﺍ ﺕﺍﺭﻴﻴﻐﺘﻟﺍ . ﺎﻴﻼﺨﻟﺍ ﻥﺎﻁﺭﺴﺩﺤ ﺔﺜﻴﺒﺨﻟﺍ ﺔﻤﺤﺘﻠﻤﻟﺍ ﺕﺎﺒﺎﺼﺇ ﺭﺜﻜﺃ ﻥﺎﻜ ﺔﻴﻓﺩﺼﻟﺍ ﹰﺎﺜﻭ ﻟﺍ ﻯﺩﻟ ﺔﻴﺴﺎﺴﺍ ﺓﺭﻭﺼﺒ ﺕﺜﺩﺤ ﻰﺘﻟﺍﻭ ﺭﻭﻜﺫ لﺍ ﺭﻤﻌﺒ 50 ﺭﺜﻜﺍ ﻭﺍ ﺔﻨﺴ .
List of tables
Table (1): The age distribution in the study 38 Table (2): The Diagnosis of All lesions in the study 42 Table (3): Frequency of neoplastic lesions in the study 44 Table (4): Frequency of Malignant Tumors 45 Table(5): Malignant Tumors versus Sex Cross tabulation 46 Table (6): Malignant Tumors versus Age Cross tabulation 47 Table (7): Frequency of Benign lesions 48 Table (8): Benign lesions versus AGE Cross tabulation 49 Table (9): Benign lesion versus Sex Cross tabulation 50
Table (10): Frequency of (CIN) 51
Table (11)Age versus CIN Cross tabulation 52 Table (12): Sex versus (CIN) Cross tabulation 53 Table (13): The frequency of non neoplastic lesions in the study 54 Table (14): Degenerative changes versus Age Cross tabulation 56 Table (15): Degenerative changes versus Sex Cross tabulation 57 Table (16): Frequency of inflammatory lesions in the study 58 Table (17): Inflammatory lesion versus Age Cross tabulation 59 Table (18): Inflammatory lesion versus Sex Cross tabulation 60
List of figures and Images
Figure (1): Sex distribution in the study 39 Figure (2): The type of biopsy in the biopsy 40 Figure (3): The site of the lesions in the study 41 Figure (4): The diagnosis divided into neoplastic and non neoplastic lesions in the study
43
Figure (4): The diagnosis divided into neoplastic and non neoplastic lesions in the study
43
Figure (5): The frequency of the degenerative changes 55
Slide images 61-68
1. Introduction and Literature Review
Various tissues of visual system contribute to lesion from inflammation to different types of neoplastic conditions.
The conjunctival lesions are the commonest lesions compared to other eye lesions, require immediate diagnosis and management, but ignorant care due to unawareness of persons can result into debility, loss of vision and occasionally life is jeopardized.
There was a previous study was done in Sudan about tumour of the eye and adnexa in 1979, 854 lesions were studied as regards their frequency, sex and age incidence, site and pathologic type and racial distinction, of 279 primary malignancy conjunctival squamous carcinoma was the commonest (50, 4 percent) while retinoblastoma formed 20.8 percent, basal cell carcinoma of eyelid 6.1 percent and malignant melanoma. Conjunctival carcinoma and allied epithelial lesions occurred much more predominant in northern than in southern Sudan(1).
From the above previous study, it is noted that the conjunctival carcinoma was the commonest, so this study will focus on histopatholgical pattern of conjunctival lesions regards their frequency, sex and age incidence, site.
1.1 Development of Eye
Evagination of the forebrain create optic vesicles that induce overlying ectoderm to form lens discs (Optic placodes).the lens discs become internalized and form the lenses, forms the anterior epithelium of the cornea and conjunctiva.(2)
The optic vesicles indent to form two layers of optic cups, which develop into the two epithelial layers of retina (The inner layer of eye ball), Including the neural retina. Mesenchyme surrounding the optic cup forms the uvea and corneosclera (The middle and out layers of the eye ball). (2)
Eyelid and conjunctiva:-
Are formed by reduplication of surface ectoderm as a result eyelid are formed, these eyelids cut of a space from cornea called conjunctival sac. The conjunctiva is thus of ectodermal in orgin.(2)
1.2 Anatomy and Histology:
The conjunctiva is amucous membrane composed of epithelium and substania propria, covers and connects the anterior surface of the eye and inner surface of the eyelid .Although the conjunctiva is a continuous layer, for descriptive purpose it is divided into a palpebral portion (Tarsal) lining the under surface of the eye lid, a forniceal portion or intermediate part forming conjunctival de sac where it reflects onto the surface of the globe, a bulbar portion covering the exposed part of the eyeball to the cornera.(3).
The epithelium of the conjunctiva is continuous with corneal epithelium and epidermis of the eyelid margin through transition zone of non keratinized stratified squamous epithelium. The conjunctival epithelium is composed of cuboidal and cylindrical cells arranged in two to five
layers ,with the addition of mucous secreting goblet cells ,which are abundant towards the fornix and nasal side of the bulbar conjunctiva. Other cells present in conjunctival epithelium include melanocyte, Langerhans cells, and intraepithelial lymphocytes. The limbal conjunctiva is the annular area that extend from the cornea to about 3mm on the bulbar portion. Branching dendritic melanocytes are abundant in this region and are often associated with melanin- containing basal epithelial cells.(3)
The substantia propria of the bulbar conjunctiva is composed of loose connective tissue and deeper dense collagenous layer. The C.T is composed of fibroblast and blood vessels, lymphatic vessels, scattered plasma-cells, eosinophils and polymorph nuclear leukocyte. The substantia propria of the palpebral conjunctiva is more uniform, is closely attached to the tarsus.(3)
Inner buddings of epithelium extend into the subepithelial connective tissue to form tubular and cystic structure, (pseudo-glands of Henle whose epithelium is made up of cuboidal cell and goblet cells. (4)
The blood vessels of substantia propria support and drain a complex capillary net work. (4)
The C.T contain myelinated and unmyelinated branches of trigeminal nerve. Close to fornices are lymphocytes aggregates, with or without reactive follicles and plasma alls. Acini and ducts of accessory lacrimal glands of WolFrin and Krause are observed in subepithelial tissue of the palpebral conjunctiva at the upper edge of tarsus and close to fornices, respectively. (4)
Nasally, a fold of loose conjunctiva forms the plica semilunaris, where smooth muscle cells and cartilage occasionally be found.(4)
Lymphatic drainage:-
Superficial, radial, and deep lymphatic vessels comprise the lymphatic channels that are located in substantial propria. Large lymphatic merge into major nasal and temporal trunks, which drains into sub mandibular, periauricular and parotid lymph node respectively. (4)
1.3 Developmental Anomalies: Dermoid tumors:-
Dermoid tumors of conjunctiva are firm, localized, elevated opaque masses that typicaly[y occur at limbus, often encroaching on the cornea.(4)
Microscopilly:-
The surface epithelium and subepithelial connective tissue present the histologic features characteristic of dermis and epidermis. A few hairs typically project from the tumor. The bulk of mass is composed of thick bundle of collagen and skin appendages are few and adipose tissue is abundant.
These are known as dermolipomas, and are usually situated in the upper outer fornix. (4)
Cyst:-
Benign-epithelium lined by inclusion cyst of the conjunctiva, usually a rise after accidental or surgical trauma or, rarelty, denovo.(4)
Choristomas:
Are congenital non neoplastic tumour growth formed by tissue elements that although cytologically normal in appearance. It consistent 22 to 33 percent of epibulbar tumour in children. (5 and6)
Several abnormal tissues may be identified( e.g. hairs, lacrimal,
serous and sebaceous glands, adipose tissue, smooth muscle, cartilage,
bone and brain).
Complex Choristomas are associated with several syndromes e.g. Nevous, sebaceous of Jadassohn, proteus syndrome, Goldenhar- Gorlin oculo-auriculovertebral syndrome.(7,8,9,10)
Ectopic Lacrimal
gland:-Lobules of lacrimal gland tissues are found outside their normal location and they may either be isolated or found as component of other Choristomas.(11)
Smooth muscle hamartoma:-
A congenital tumor composed of spindle-shaped smooth muscle cells has been reported from the inferior fornix and tarsal conjunctiva region.(12) Histopathologic examination reveal large bundles of smooth muscle intermixed with fibrous stroma and lobules of adipose tissue.
Congenital vascular lesions:
Congenital vascular lesion of conjunctiva includes capillary telangiectasias, vascular tortuosrties and varix, and lymphangiectases. They present a part of conjunctival systemic Malformation syndrome termed phakomatoses, including Sturge -Weber syndrome , Louis Bar syndrome and ataxia telangiectasia).(3)
1.4 Inflammation of Conjunctiva:
Inflammatory lesions of conjunctiva rarely give rise to the type of diagnostic or therapeutic problem that requires excision and histopathologic study.(4)
Ligenous
Conjunctivitis:-Is peculiar form of chronic pseudomembranous conjunctivitis that present as woody induration of the eyelid and formation of pseudomembrane on tarsal conjunctiva.(13,14)
The cardinal features histologically are presence of large hyaline masses (Simulate Amyloid).(13,14)
Inclusion
Conjunctivitis:-Is seen in adult as acute or chronic inflammation. It is produced by Chlamydia and it shows microscopic appearance of follicular conjunctivitis indistinguishable from viral infection. The diagnosis is based on the finding of so called (Halberstaedter –prowazek inclusion) on conjunctival scrapings. However, Infections may produce significant conjunctival scaring, lead to dry eye and corneal o pacification. (15)
Sjogren’s syndrome:
Manifests itself in the conjunctiva by metaplasia of epithelium, associated with a decreased number of goblet cells and polymorphic inflammatory infiltrate in the stroma. (16)
Actinic granuloma:
It is foreign body granulomatous reaction against the elastototic collagen.(17)
Chalazion:-Is an extremely common lesion. It represent lipogranuloma that develops in and about a meibomian gland, presumably as a consequence of the combined effects of obstruction , and non specific infection of the gland, the sebaceous material discharging into tarsal conjunctiva provokes an intense granulomatous inflammatory lesion.(4)
Sarcoidosis:
Is a non-caseating granulomatous inflammation that affect the conjunctiva in one fourth patients with granulomatous inflammation. (18)
1.5 Tumours of the conjunctiva:-
Classification:-Conjunctival tumors are classified as benign, premalignant, and malignant.
The most frequent conjunctival tumours are epithelial, melanocytic, and lymphoid proliferation and choristomas .Among the epithelial tumors, intraepithelial neoplasia and squamous cell carcinoma are mainly encountered in adult while Papilloma and choristoma are mostly found in children. Forty percent of excised pigmented lesions are nevi, and approximately thirty six percent are melanoma. A precursor of melanoma, primary acquired melanosis, is a distinctive melanocytic lesion of conjunctiva.(3)
Lymphoid proliferations are less frequent in the conjunctiva than in the orbit. A wide variety of soft tissue tumors may arise from the substantia propria of conjunctiva.(3)
Epithelial neoplasms:- A-Papilloma
Definition: Conjunctival Papilloma is a benign acquired papillary lesion.
It is composed of branching fibrovascular cores covered by acanthotic, non keratinized squamous epithelium that contains variable number of mucin secreting cells. Synonyms include squamous cell Papilloma, conjunctival Papilloma, infectious Papilloma, and conjunctival wart.
Clinical features:
Papillomas may develop at any age but are more frequent in children. They are solitary or multiple, unilateral or bilateral. They are arising from semilunar fold at the inner canthus or from the fornix.(3)
There may be secondary or multicentric involvement of the bulbar and palpebral conjunctivae. Human Papilloma virus serotype 6.11 and 16 has been demonstrated in 50 to 92 percent of the lesions.(19)
Microscopic Findings:-
Squamous Papilloma is exophytic lesions that are often covered by multilayered, non keratinized squamous cell with variable number of mucus secretary goblet cells. Acute inflammatory cells often permeate the exposed epithelium. Although the HPV is demonstrated in these lesion but koliocytesis is uncommon. Papillomas a rising in limbal region often are sessile and covered by acanthotic squamous epithelium. It may associate with mild to moderate dysplasia, but it has no risk of malignant transformation in children.(3)
An endophytic variant of Papilloma, inverted mucoepidermoid Papilloma, is characterized by invaginated lobules of proliferating, non keratinized squamous epithelial cells containing goblet cells.(20)
Treatment and prognosis:-
- Surgical excision and cryotherapy.
- Extensive and recurrent Papilloma may be treated with topical interferon and mitomycin or oral cimetidine.(3)
Keratoacanthoma:-
Definition: Is uncommon, rapidly growing, crater-like squamous cell proliferative tumor squamous cell carcinoma and pseudo epitheliomatous hyperplasia.(3)
Clinical features:-
The lesion tends to originate in the sun-exposed part of the bulbar conjunctiva.(21)
Microscopic findings:-
The lobules of proliferating squamous epithelium grow upward and inward, the epithelial cells may have glassy appearance, with vesicular nuclei and prominent esoinophilic nucleoli, true parakeratosis is rare. It may be infiltrated by acute and chronic inflammatory cells. (21)
Differential diagnosis:-
Keratoacanthoma may be confused with and difficult to differentiate from squamous cell carcinoma. The biologic behavior of the lesion will differentiate Keratoacanthoma from well differentiated squamous cell carcinoma of the conjunctiva.(22)
Treatment and prognosis:-
Treatment of choice is surgical removal, followed by cryotherapy. Recurrences are rare.
C: Hereditary benign intraepithelial Dyskeratosis: (HBID)
-Is rare, autosomal dominant disease with incomplete penetrance .It is characterized by acanthotic and dyskeratotic epithelium invading the conjunctival and oral mucosa.(3)
-Called Witkopvor Sallman syndrome and benign hereditary dyskeratosis. (3)
Clinical features:-
In childhood, bilateral, horseshoe-shaped conjunctival lesion, involve the inter palpebral regions.
The disease has chronic relapsing course, it is resistant to medical and surgical intervention.(3)
Microscopic findings:-
- Conjunctival epithelium is replaced by large squamous like cells and dyskeratotic cell without nuclear atypia.
- Malignant transformation has not been reported.
- Associated with chronic inflammatory cellular infiltrate in subepithelial connective tissue.(3)
Ultrastructural findings:-
Reveal the presence of numerous vesicular bodies in immature dyskeratotic cells. Cellular inter digitation and desmosome disappear in mature dyskeratotic cells.(23)
Differential Diagnosis:-
Although the lesion resembles cojunctival epithelial dysplasia, individual cells in HBID do not have atypical changes. In addition, the presence of affected family members, bilatrality and involvement of oral mucosa help to distinguish theses two lesions.(3)
Treatment and prognosis:-
Surgical excision, but recurrence is common. Malignant changes have not been observed.(3)
D: Epithelial Cysts:-
The majority of cojunctival epithelial cysts are acquired, although some are congenital. Cysts are acquired secondary to surgical or accidental trauma, foreign body and chronic inflammation. (24)
They are more located on the nasal conjunctiva and lower fornix. They are lined by non keratinized squamous epithelium that contains a variable number of mucous- secreting goblet cells. Simple excision is usually curative.(3)
E: Nonspecific Keratotic (Leukoplakic) lesions:-
Include a variety of isolated grayish white epithelial lesions of bulbar conjunctiva that have no malignant transformation. Called Bitot spot (area of squamous metaplasia and hyper keratosis). They are associated with vitamin A deficiency and with Sjogren’s syndrome.(3)
F: Pseudoepithiliomatous (pseudocarcinomatous) Hyperplasia:-
Is a reactive proliferation of surface epithelium secondary to inflammatory or infectious processes. The proliferative squamous epithelium forms irregular lobules with variable degree of acanthosis and keratinization. The epithelial cell may exhibit reactive changes and increased mitotic changes, and indistinct border between the proliferative epithelial cells and subepithelial connective tissue. (3).The latter is heavily infiltrated with mixed acute and chronic inflammatory cells. Special stains for fungi or bacteria may disclose the causative organism.(25)
Pseudo adenomatous hyperplasia refers to gland-like proliferation that may mimic mucoepidermoid carcinoma. (26)
Leukoplakic lesions (Ultraviolet light related):- degenerative lesions:-
This group of Leukoplakic lesions of limbal conjunctiva features acanthosis and dysplasia of epithelium overlying elastotic degenerated substantia propria. Due to ultraviolet light damage, WHO classifies these lesions as actinic keratosis.(27)
Pterygia
are fleshy lesions arising interpalpebral region of the bulbar conjunctiva and involve the cornea. Surface epithelium may be atrophic or thickened or show dysplastic changes and keratosis, with subepithelial degenerative elastotic fiber and increased visualization. (3)Pinguecula:-
Is very common degenerative process affecting primary subepithelium connective tissue of the bulbar conjunctiva in the interpalpeberal region. Present as elevated yellowish lesion, surface epithelium is atrophic or thickening.(4)
Microscopical findings:
Actinic diastesis of band like zone beneath epithelium over the lesion may be atrophic or acanthotic with dyskeratosis.(4)
Conjunctival intraepithelial neoplasia (CIN):-
Includes a wide range of neoplastic intra epithelial changes ranging from dysplasia to full thickness epithelial neoplasia or carcinoma in situ-synonyms include mild, moderate and severe dysplasia, carcinoma in situ or ocular surface squamous neoplasia, intraepithelial epithelioma.(28)
General features:-
Development of CIN is associated with ocular pigmentation, exposure to petroleum product and cigarette smoking, long standing use of cyclosporine therapy in organ transplantation recipients. HPV type 6 and 11 are found in 38 % and HPV16 and 18 in 30 to 58 % of patients with conjunctival dysplasia. (29)
Clinically,the lesion is sharply demarcated at the limbus, it is pink and have a raspberry like configuration (30)
Microscopic findings:-
Intra epithelial dysplastic changes originate in basal layers and extend to the surface, the epithelial cell become large squamous cell, small epithelial, spindle - shaped epithelial cells. Keratinization and dyskeratosis are not common features of CIN. Atypical mitosis is
frequent and maybe located at all levels of the epithelium. The epithelial basement membrane remains intact. The intraepithelial dysplastic changes are graded as mild, moderate, or severe depending on the thickness. Rarely, Koilocytes are identified.(30)
Proliferating cell nuclear antigen and P53 immuno staining and (Argyrophilic nucleolar organizer region) staining are used for grading of dysplastic lesions. (31)
Treatment and prognosis:-
- Complete surgical excision.
- Recurrences are seen in 10 to 70 percent of cases with incomplete surgical excision.
- In cases with diffuse involvement and recurrence, Adjunctive chemotherapy with topical application of mitomycin C, 5 fluorouracil and interferon alpha2b have been used.(32,33)
Squamous cell
carcinoma:-Squamous cell carcinoma of the conjunctiva is invasive keratinizing tumor arising from the epithelial conjunctival surface. They tend to recur but rarely metastasize expect in advanced neglected cases.(3)
General Features:-
The incidence varies from 0.03/100.000 population in United States to 3.5/100/000 in Uganda. Usually present during sixties with male predominance. Increased incidence in African countries in patient who are immunodeficiency virus (HIV) seropositive.(34,35)
Although most SCCs originate from actinic related Keratotic lesions, there are other predisposing conditions, including xeroderma pigmentosa, albinism, toxic exposure to chemicals and physical factors. Polymerase chain reaction and insitu hybridization studies on tumor tissue have
revealed the presence of HPV 16 and HPV18 in 55percent of patients with SCC. (36)
Clinical Features:-
- The tumor occur in the bulbar conjunctiva reaching limbus in the inter- palpebral region.
- They are gray whitish, exophytic, crater like appearance.(37)
Microscopical finding:-
Well differentiated SCC is characterized by infiltrating lobules, nests, and cords of variable size, extending from the surface neoplastic epithelium into the subepithelial connective tissue. The epithelial lobules display keratinization with either the presence of cells arranged concentrically around a central focus of a cellular keratin or multiple foci ofcellula keratinization. The large squamous cells have esoinophilic or clear cytoplasm and intracellular bridges and many show individual cell dyskeratosis. The cells show hyperchromatic nuclei and prominent nucleoli, the mitotic activity is usually low with abnormal mitotic figures. In heavy pigmented patients, melan in pigment maybe found within the benign and malignant epithelial cells, simulating melanoma.(3)
Immunohistochemical finding:-
The neoplastic squamous cells express high molecular weight cytokeratin and epithelial membrane antigen and other epithelial marker. The main use of these antibodies to differentiate squamous cell carcinoma from other undifferentiated neoplasms.
Special study:-
DNA and cytomorphometric analyses show that squamous cell carcinoma cells are most frequently aneuploid(38) ,while hyperplastic epithelial lesions are non aneuploid. Other molecular markers such as epidermal
growth factor receptor, transforming growth factor alpha cyclin DI, and P53 may provide valuable prognostic information.(38)
Treatment and prognosis:-
Complete surgical excision with 3 to 5 mm surgical margins is the treatment of choice. Recurrences, which occur in approximately 6 % of cases, have a slow growth rate of 6 months to one year after original excision. Topical 5 fluorouracil has been used to treat cases with diffuse involvement, incompletely excised lesions, and recurrence. (39)
Deeper structures are locally invaded with varying frequency, including sclera (37%) intraocular content (13%) and orbital tissue (11%).
Risk factors for metastasis are large size, neglected tumor, and multiple recurrences.(39)
Initial site of metastasis includes the parotid , submandibular , preauricular and cervical lymph nodes, other site include lung and bone.(39)
Pathologic staging of squamous cell carcinoma of conjunctiva:- Primary Tumor (T):
TX Primary tumor can not be assessed. TO No evidence of primary tumor. Tis carcinoma insitu.
T1 Tumor 5 mm or less in greatest diameter.
T2 Tumor more than 5 mm in greatest diameter without invasion. T3 Tumor invades adjacent structure, excluding the orbit.
Regional lymph node (N):-
NX regional lymph node can’t be assessed. N0 No regional lymph node metastasis. N1 Regional lymph node metastasis.
Distant Metastasis:-
MX Distant metastasis can not be assessed. M0 No distant metastasis.
M1 Distant metastasis.
Histopatholgical grading:-
G x Grade can not be assessed. G 1 Well differentiated.
G 2 Moderately differentiated. G 3 Poorly differentiated. G 4 Undifferentiated.
• Data reference 40
Variants of squamous cell carcinoma: Mucoepidermoid carcinoma: MEC:-
Mucoepidermoid carcinoma of the conjunctiva is rare neoplasm that clinically resembles squamous cell carcinoma (41). The average age of clinical presentation is 67 years. Usually it develops from the limbus and bulbar conjunctiva and characteristically shows local aggressiveness (42). Histologically, there is an admixture of epidermoid cell, intermediate cells, and mucus producing cells. In infiltrating area, the neoplastic cells may surround the pools of mucin that stain brightly with alcian blue,
colloidal iron and mucicarmine method. The presence of squamous pearls is the exception rather than rule.(42)
The recommended treatment is wide local excision with free surgical margin. Rapid recurrence is usually observed. Plague radiotherapy with 125 has been used for recurrent lesion. MEC is aggressive locally and can metastasize to regional lymph node, lung, and bone.(43)
Spindle cell carcinoma:-
Spindle cell carcinoma of the conjunctiva, also referred as polypoid carcinoma of the conjunctiva, resembles a spindle cell fibroblastic- like tumor with subtle continuity with the surface epithelium, it presents as localized, elevated smooth surface epithelium, reddish lesion arising from the limbus or bulbar conjunctiva in the elderly patients .(44)
Histologicaly: Shows acanthotic epithelium with infiltrating cells has
spindle- shaped configuration, oval vesicular nuclei, and large basophilic or esoinophilic nucleoli. It associated with foci of dysplasia and even carcinoma insitu, mitotic figures are variable, associated with desmoplasia and chronic inflammatory response.(45)
Immunohistochemistry demonstrates the presence of keratin, vimentin, actin filaments and epithelial membrane (EMA).Electron microscopy demonstrates the true epithelial nature of the lesion (desmosomes and tono filament.(45)
Adenoid squamous cell carcinoma:-
Adenoid squamous cell carcinoma is characterized by islands of atypical squamous cell with foci of acantholysis and pseudo glandular spaces. Synonyms include acantholytic squamous cell carcinoma or adenocanthoma and pseudo glandular squamous cell carcinoma.(46)
Patient present with mass at the limbus or bulbar conjunctiva that is associated with severe inflammation, these tumors have aggressive behavior and they may recur or infiltrate the deep orbital tissue. Treatment of choice is surgical excision with controll of margin(3).
Other carcinoma of the conjunctiva:- Basal cell carcinoma:-
Rarely, basal cell carcinoma arises from the conjunctiva without any adjacent lesion in the skin of the eyelid.(47)
The tumor is reported in men aged 24 to 66 years, it presents as a white nodular growth of conjunctiva.(48)
Microscopically:-
Nodular and cystic tumors composed of atypical basloid cell, indistinguishable from tumor that originate from skin.
Sebaceous carcinoma:-
The neoplasia may be caused by intraepithelial transformation of cojunctival cells or the result of spontaneous regression of underlying meibomian gland carcinoma. In most of cases, there is an occult sebaceous carcinoma with secondary pagetoid spread into the cojunctival epithelium.(3)
Tumor differentiated by Immunohistochemical of milk fat globule, breast carcinoma antibody, EMA and oil red O stain (in frozen section).(3)
Analysis of isolated reported cases indicated that this lesion may remain in site for prolonged period without evolving to an invasive carcinoma, cryotherapy is treatment of choice. (3)
Lymphoepithelioma- like carcinoma:-
Is rare tumor in the conjunctiva, is strongly associated with Epstein- Barr virus.(3)
Histologically
Characterized by nonkeratinizing, undifferentiated squamous cell carcinoma with lymphocytic infiltration. Clinically lesions are white- yellow and behave as aggressive tumorss.(3)
Melanocytic Tumor:
Melanocytic lesions are the second most common cojunctival lesions. Although the benign lesions outnumber malignant tumor, a correct interpretation of the histopathologic finding is important to guide clinical and surgical management. (3)
Classification of the melanocytic lesions of the conjunctiva: I. Congenital:
• Epithelial:
o Racial pigmentation
o Benign epithelial melanosis o Ephelis • Subepithelial: • Ocular melanocytosis • Oculodermal melanocytosis II. Nevi: • Congenital • Acquired o Junctional o Subepithelial o Compound • Variants o -Spindle/epitheloid
o -Blue nevus o -Combined nevus o -Melanocytoma
III. Acquired melanosis:-
o Bilateral o Racial o Metabolic o Toxic o Unilateral:- o Secondary melanosis
o Primary Acquired melanosis
1V Melanoma:-
o In primary acquired melanosis o De novo
o In nevi
o Secondary from uveal melanoma. o Metastatic (3)
Nevi:
General Features:-
Cojunctival nevi first appear in childhood as small, circumscribed, flat lesion which may or may not be pigmented (49), most of locations of cojunctival nevi are the bulbar region, and rarely, the tarsal conjunctiva .Nevi are capable of growth especially during puberty and pregnancy.(3)
Microscopic Findings:-
Junctional nevus is composed of contiguous nests of round to spindle – shaped melanocytes that have oval nuclei and small nucleoli, aligned along the basal cell region.(3)
Cells of the more common compound nevus are present in the both epithelium and subepithelial connective tissue, these nevi characteristically have cells with intra nuclear inclusions and cysts of variable size lined by cuboidal cells and goblet cells that are large and have prominent basophilic nucleoli. These cells are located at the basal layers of the epithelium and extend into the superficial stroma, they are as manifesting junctional activity. Mitotic activity is absent .Inflammation is a common finding.(3)
The last stage of cojunctival nevus ontogeny is represented by nevus cells with bland nuclei entirely located in the subepithelial connective tissue. These subepithelial nevi are usually non pigmented. Balloon cell nevus is nevus which is composed lipidized nevus cell.(49)
Malignant transformation of a nevus occur in 1 of 150/000 lesions. (50) Despite careful histopatholgical examination, a group of indeterminate melanocytic lesions exists that can not be classified by pathologist as benign or malignant, because common nevi of conjunctiva may change colour, become elevated, and grow large particularly during puberty and adolescence. (51)
The absence of an atypical intraepithelial component, atypical mitotic figures, and necrosis, however is helpful for the differentiation from melanoma.(3)
Treatment and prognosis:-
In children, because conjunctival nevi rarely progress to melanoma, surgical excision is not indicated. Indication of surgical excision include
newel acquired pigmented lesions in adult, change in pigmentation and increased vascularity. Biopsy is only indicated in very large lesion. Rate of recurrence is 2.7 percent following local excision.(52)
Nevus
Variants:-Spindle and epitholoid cell nevus.
Is counterpart of spitz epitheloid nevus of skin(53) . It is seen in childhood as non pigmented lesion with nodular appearance that may or may not be associated with rapid growth. It has uniform, large epitholoid- like cells with pigmented spindle cells that exhibit (wind- blown) pattern. The cells located in subepithelial connective tissue. (54)
Blue nevus and cellular blue nevus:-
These lesions are bluish brown because of superficial location. Pigmented spindle and dendritic melanocytic nevus cells extend within the collagenous stroma. (55)
Combined nevus:-
It has been recognized recently, it combine the histologic features of compound or subepithelial acquired melanocytic nevus and pigmented blue nevus.(56)
Melanocytoma (Magnocellular nevus):-
Is rare, benign, deeply pigmented melanocytic nevus of the optic nerve and uveal tissue that rarely may arise in conjunctiva, it is composed of large, polygonal melanocytic cells heavily loaded with pigment that obscure the nuclei.(57)
Other Benign Melanocytic Lesions:-
Racial Pigmentation and Benign Epithelial melanosis:-
Conjunctival pigmentation seen in pigmented individuals is termed racial pigmentation, racial melanosis, complexion –associated conjunctival pigmentation, the incidence is high in blacks. microscopically the basal layer of epithelium is pigmented and melanin typically accumulates in the supranuclear location.(3)
Ephelides:-
Ephelides or freckles are congenital focal lesions found in the interpalpebral conjunctivas that become pigmented in childhood and adolescence.(3)
Histologically, the conjunctival epithelium has normal appearance except the presence of a well –circumscribed area of hyperpigmented basal cell. Pigmentation remains stable over time.(3)
Primary acquired Melanosis:-
Primary acquired melanosis (PAM) is a clinicopathologic term used to describe a unilateral intraepithelial proliferation of abnormal melanocyte of conjunctiva that possesses variable biologic behavior, from benign to locally spreading, to malignant.(58)
General Features:-
The epidemiological study suggests that PAM is frequent lesion of the conjunctiva seen in about 36 % of adult Caucasians (59). Approximately one third of cases of PAM confirmed histologically develop into melanoma.(60)
Clinical Features:-
PAM is a slowly progressive lesion with golden- brown, flat pigmentation of the conjunctiva in middle age white patients. The common location is bulbar conjunctiva but also forniceal and palpebral conjunctiva is involved (3).
Microscopic Findings:-
Usually, there is spectrum of epithelial involvement by abnormal melanocyte, which produces melanin that transfer or phagocytosed by adjacent epithelial cells. With progression, melanocytes proliferate as a layer of transformed cells in the basal layer, termed basilar melanocytic hyperplasia, while basilar nests push the overlying epithelium without extending into superficial epithelium, may form intraepithelial nest, or atypical melanocyte move upward into superficial epithelial layers, adopting a pagetoid growth pattern. The individual atypical melanocytes have retracted cytoplasm, nuclei are usually larger that the those surrounding epithelial cells, with clumping of the chromatin and prominent basophilic nucleoli. Atypical melanocyte may be: Spindle cell, polyhedral cell with small round nuclei and scanty cytoplasm (3).
Microinvasive melanoma develops in areas of marked confluent intraepithelial melanocytic atypia. Actinic damage of the collagen and foci of benign nevus cells are observed in 20 percent of cases (61).
PAM is currently classified as PAM without atypia and with atypia, PAM with atypia is divided into low risk and high risk, based on ether the absence or presence of atypical melanocyte with epitholoid configuration or an intraepithelial growth pattern resembling intraepithelial melanoma insitu (62)
Immunohistochemical findings:-
Is useful to differentiate PAM from non melanocytic lesion. The melanocyte cells stain with HMB45, S-100, vimentin, Melan A, and are negative for cytokeratin and EMB (3) .
Ultrastructural findings:-
Although electron microscopy is not routinely used for diagnosis of PAM (62).
PAM without atypia shows melanocyte with dendritic process and transferred melanin in the epithelial cells is regarded as grade1. Grade 2 PAM consists of melanocytic cells having shorter dendritic process, and immature melanosomes, irregular nuclei and large nucleolus. Grade 3 PAM is presence of epitheloid cells(3) .
Treatment and prognosis:-
Any nodular lesion, enlarging flat lesion, pigmented lesion of palpebral conjunctiva or clinically suspicious pigmentation should be either completely excised or biopsied based on lesion size. Based on diagnosis and the completeness of excision, patient may receive atopical mitomycine and 5- Fluorouracil(63) .
If progression of PAM to melanoma is not observed after first 10 years after diagnosis, the patient is at low risk for the development of malignant melanoma (64).
Melanoma:-
General Features:-
Melanoma of the conjunctiva accounts for approximately 2 percent of ocular malignancies (65). It is second most frequent malignant neoplasm of the conjunctiva after SCC. The development of melanoma in black is
rare (66). Melanoma may originate from preexisting PAM, from nevi, or de novo. Most melanoma of conjunctiva are heavily vascularized pigmented, nodular or elevated tumor that usually arise in areas of preexisting conjunctival pigmentation (67)
The average of age at time of diagnosis is the fifth decade .Melanoma is extremely rare in children and adolescents (68)
Although they are most frequent in the interpalpebral region of the bulbar conjunctiva, they may arise from fornix palpebral conjunctiva, and inner canthus (69)
Microscopic Findings:-
By definition, the invasion of atypical melanocytes into the subepithelial connective tissue, qualifies the lesion as melanoma. (3)
The tumor cells are bizarre, polygonal, epithelial cells with esoinophilic cytoplasm, atypical large vesicular nuclei and prominent esoinophilic nucleoli. Mitotic activity may be present. A mixture of other cell types including small polyhedral cells, smaller spindle cells with oval nuclei, and balloon cells with clear cytoplasm containing lipid and nuclear indentation, may be present. The degree of pigmentation and necrosis is variable.(3)
An important histologic feature is whether or not PAM is present. Because large melanoma at the time of excision show an ulcerated surface, examination of the epithelium at the edge of excision may reveal finding of PAM such as pagetoid spread and atypical intraepithelial epitheloid melanocytes.(3)
Immunohistochemical Findings and special studies:-
Are valuable to confirm the diagnosis of non pigmented melanoma and for differentiate melanoma from other primary or secondary undifferentiated malignant neoplasm of conjunctiva.(3)
Conjunctival melanoma cell are positive for HMB45, vimentin, S 100 protein and Milan A.(3)
Aggressive melanoma with epitheloid cells shows focal positivity for cytokeratin. Studies of nucleolar organizer regions have suggested a cut off value of 4.0 (mean silver staining of nucleolar organizer regions per cell) to differentiate melanoma and PAM with atypia from nevi and PAM without atypia.(69)
Treatment and Prognosis:-
Primary treatment of malignant melanoma of the conjunctiva consist of complete surgical excision of the tumor and application of cryotherapy to the surgical edges and base of the lesion.(3)
Post operative radiotherapy and chemotherapy are additional treatment for patient in whom the tumor can not be excised completely or in whom there were previous recurrence or melanoma with PAM with atypia. Exenteration of orbit is used as palliative procedure for advanced local disease.(70)
Tumor prognosis thickness has recently become 0.8 cm from surface of lesion to the deepest margin of tumor invasion. The death rate is two time higher with tumor thickness of 1 to 4 mm thick. Histologic factor suggesting a poor prognosis include origin from PAM with pagetoid intraepithelial spread, tumour composed epitheloid cell rather than spindle cells, greater than 5 mitotic figure per 10 high power field, lack of lymphocytic host response, and presence of vascular, lymphatic or perineural invasion, invasion of sclera, orbit, and cornea and Anatomic location of tumour other than limbus region.(71)
Conjunctival melanoma spread Periauricular intraparotid gland lymph nodes followed by submandibular and cervical lymphnodes, followed by lung, liver, skin, brain, and bone metastasis. (68)
Staging:-
Is based on complete resection of the primary site and histologic study of the margins and deep tissue.
Staging of Melanoma of conjunctiva clinical calcification (c TNM) Primary Tumour (T):-
TX Primary tumour can not be assessed.
T0 No evidence of primary tumour.
T1 Tumour (s) of bulbar conjunctiva occupying more than one Quadrant.
T3 Tumor(s) of conjunctival fornix and /or palpebral conjunctiva and/ or
Caruncle.
T4 Tumour invades eyelid, cornea, and/ or orbit.
Regional lymph node. (N):-
N x Regional lymph node can not be assessed. N0 No regional lymph node metastasis.
N1 Regional lymph node metastasis.
Distal Metastasis (M):-
M x Distant metastasis can not be assessed. M0 No distant metastasis.
Pathological classification (p TNM) Primary tumour (pT):-
PT x primary tumor can not be assessed. PT0 No evidence of primary tumour.
PT1 Tumour(s) of bulbar conjunctiva occupying one quadrant or less in Thickness.
PT2 Tumor(s) of bulbar conjunctiva occupying more than one quadrant And 2mm or less thickness.
PT3 Tumor(s) of conjunctival fornix and /or palpebral conjunctiva and/ or Caruncle or tumour(s) of bulbar conjunctiva, more than 2mm in Thickness.
PT4 Tumour invades eyelid, cornea, and/ or orbit.
Regional lymph node (pN):-
PN x Regional lymph node can not be assessed. PN0 No regional lymph node metastasis.
PN1 Regional lymph node metastasis.
Distant Metastasis (pM):-
PM x Metastasis (PM) PM0 No distant metastasis. PM1 Distant metastasis
Histopathologic Grade (G):-
G x Origin can not be assessed. G0 Primary acquired melanosis.
G1 Malignant melanoma arises from nevus.
G2 Malignant melanoma arises from primary acquired melanosis. G3 Malignant melanoma arises denovo
*Data reference 40.
Soft Tissue Tumours:-
The non epithelial tissue of conjunctiva include vascular and lymphatic structure, prephral nerves, adipose tissue and mesenchymal elements, all of which give rise to several types of soft tissue tumour, most of them are benign with exception of botryoid variant of embryonal rhabdomyosarcoma,(72)
Malignant fibrous histocytoma and kaposi’s sarcoma involving conjunctiva in patient with AIDS.(72)
Vascular
Tumours:-Are frequently seen clinically, hemangioma of capillary type may be isolated or associated with a large capillary hemangioma affecting the eyelid and perioccular skin.(3)
Types of hemangiomas:-Cavernous hemangioma:-
Are composed of enlarged, blood- filled vessels that are lined by endothelial cells and are surrounded by pericytes and scattered smooth muscles cells, arranged in aloose collagenous stroma.(3)
Pyogenic granuloma:-
Is hyperplastic vascular lesion usually occur following surgery, as foreign body reaction or from inflammatory disease associated with chalazion, typically, the lesions are fleshy, polypoid and red or yellow. They show a
lobulated appearance of anastomosing capillary vessels with variable edematous collagenous stroma, the stroma contains acute and chronic inflammatory cells, and the surface is often ulcerated. (3)
Lymphangiomas of
conjunctiva:-Should be a part of larger lesion affects the orbit and the eyelids.
Microscopically:-
The lesion shows a sinusoidal pattern of vascular empty spaces lined by flat endothelial cells without pericyte.(3)
Myxoma:-Myxoma are rare benign mesenchymal tumour that may originate any where, including the eye and conjunctiva, they are painless, circumscribed, smooth gelatinous lesions of the bulbar (temporal) conjunctiva.(73)
Light microscopy show hypocellular lesions composed of stellate-and spindle- shaped cells with delicate cytoplasmic process and small intranuclear vacuoles. Between stromal cells, there is Alcian blue- positivity, hyaluronidase. Sensitive Acid mucopolysacharides.(73)
Treatment:-
Simple local excision is curative, No recurrences have been reported.(74)
Fibrous Histocytoma:-
Is a common mesenchymal neoplasm of ocular adnexa that arise from the soft tissue of the conjunctiva. Benign and malignant variants of F.H.C of conjunctiva have been reported. F.H.C arises from the limbus or epibulbar conjunctiva and have a fleshy, yellowish, nodular appearance. (75)
Histologically:
Benign fibroushistocytoma
Is a proliferation of bundle of spindle cells arranged in storiform pattern, with foam cells , hemosidren pigment and multinucleated giant cells.(76)
Malignant fibrous histocytoma:
Histologically, are large in size, categorized into storiform, pleomorphic, myxoid, inflammatory, giant cell and angiomatoid variants.(76)
Treated by complete surgical excision.
Embryonal Rhabdomyosarcoma, Botryoid subtype:-
Is an embryonal rhabdomyosarcoma that affects mucosal surfaces including the conjunctiva(77) . Children present with rapidly enlarged lesion with fleshy, gelatinous mass without associated inflammatory redness or lid oedema.(77)
The myxoid hypercellular tumor is separated from the surface epithelium by multiple layers of neoplastic spindle cells and round rhabdomyoblast showing an esoinophilic cytoplasm and enlarged, hyperchromatic and pleomorphic nuclei. The stromal matrix shows mucopolysacharides and edema resembling cystic spaces. Cross striation are seen in less than 10 percent of cases, the cells are positive for desmin and muscle- specific actin, vimentin.(77)
Kaposi’s sarcoma:-
Kaposi’s sarcoma of the conjunctiva and eyelid occur in about 20 percent of patients with AIDS, it may be the first manifestation of the disease. The incidence of Kaposi’s sarcoma in ADIS. Patients has declined with the use of hyperactive antiretroviral therapy (HAART).(78)
Clinicopathological classification of ocular adnexal Kaposi’s sarcoma proposed by Dugel et al is useful for diagnosis, management, and prognosis after excision of kaposi’s sarcoma.(78)
Type 1 Kaposi’s sarcoma:-
Lesions are patchy and flat less than 3mm in thickness, composed of thin and dilated vascular channels filled with erythrocytes, lined by endothelial cells without spindle cells or mitotic activity .(79)
Type11 Kaposi’s sarcoma:-
Lesion consist of flat tumour less than 3mm thickness, empty vascular channel lined by plump , fusiform endothelial cells with hyperchromatic nuclei but no mitosis and few spindle cells.(79)
Type111 Kaposi’s sarcoma:-
The lesions are nodular, measures more than 3mm thickness, histologically composed of packed spindle cells with hyperchromatic nuclei and mitotic figures, and slit- like spaces containing erythrocyte.(79)
Treatment:-
Local excision for isolated conjunctival lesion or large lesion comprises the vision. Local therapy should include excision with 1and 2 mm of normal tissue followed by cryotherapy. Alternative treatment includes cryotherapy, radiotherapy, and local injection of chemotherapy or interferon alpha.(80))
Lymphoid Tumours:-
Lymphoid tumor of conjunctiva as primary tumor or secondary infiltrate as apart of systemic disease. They include a spectrum of benign, malignant and atypical or indeterminate lymphoid proliferations.
Conjunctival lymphoid lesion account 20 percent of ocular adnexal tumour. (81)
Patient present with painless mass associated with photo phobia and redness and irritation with an incidentally found conjunctival lesion. Most common sites are fornix, inner canthal area, and bulbar conjunctiva in 25 percent of cases. (81)
Most conjunctival lymphomas are classified into an extranodal marginal zone lymphomas (EMZL) of mucosa-associate lymphoid tissues (MALT).
EMZL should be differentiated from less common type of conjunctival lymphoma like mantle cell lymphoma, follicular lymphoma, lymphoplasmocytic lymphoma, and B- cell chronic lymphocytic leukaemia and small lymphocytic lymphoma.
The incidence of non ocular lymphoma in patients with conjunctival lymphoma is less than 40 percent.(82)
EMZL has an indolent course without extraocular involvement in about 70 percent of cases. Patient with mantle cell lymphoma has aggressive behavior.(82)
Plasmacytoma:-
The conjunctival maybe affected by multiple myeloma or may rarely the site of localized plasmacytic proliferation. (83)
Localized disease has been termed solitary plasmacytoma or primary extra medullary solitary plasmacytoma.
Tumours are circumscribed reddish arise from fornix, bulbar, or tarsal conjunctiva , it has indolent course and managed conservatively.(83)
Metastatic tumour of the conjunctiva:-
Metastasis to the conjunctiva in patients with advanced systemic malignancy is rare. The most frequent primary sites are breast, lung, and skin (cutanous melanoma). (84). Metastatic lesions are solitary either bulbar or palpebral . Most metastic melanoma to conjunctiva should not be confused with PAM. Survival after diagnosis is poor.(84)
Objectives
General objectives:-
To study patients with conjunctival masses in the study area from January 2007 to December 2009 in Khartoum state, with the objective to determine the different histopatholgical patterns corelating age and sex incidence.
Specific Objective:-
1. To review the histopatholgical patterns of conjunctival masses.
2. To determine the frequency, age and sex incidence correlated to each conjunctival mass.
3. To determine most common site of conjunctival masses. 4. To determine the type of biopsy done for conjunctival masses.
2. Methodology
2-1 study design:-
This study is descriptive retrospective recorded data bases study.
2-2 study area:-
This study was conducted at the national health laboratory, department of histopathology. It is major public section laboratory in the country, providing nationwide diagnostic training and research services.
2-3 study population:-
All patients come with conjunctival mass in the department of histopathology in the study area, from January 2007 up to December 2009.
2-4 inclusion criteria:-
All cases with conjunctival biopsies of full records and histopatholgical slides.
2-5 Data collection:-
Data were collected from the patients request form into a predesigned questionnaire with detailed personal history, site, size and duration of conjunctival masses. The histopathological slides were collected and reviewed to confirm the diagnosis of conjunctival biopsies by experienced Histopathologist.
2-7 Data analysis and statistics:-
The data were analyzed electronically using computer program SPSS version 10.
Ethical consideration:-
3. Results
Table (1): The age distribution in the study: ( n=130)
Percent Frequency The range 12.3 16 <10 10.0 13 10-19 23.1 30 20-29 19.2 25 30-39 7.7 10 40-49 6.9 9 50-59 8.5 11 60-69 11.5 15 >70 0.8 1 Non-specified age 100.0 130 Total
Figur fema 36% re (1): Sex ale % Sex dist x distribut tribution i ion in the in the stu study udy male 64%
Figure ( 1 (2): The t 71% 13% T type of bio 16% Type of Bio opsy in the opsy e biopsy undetermin Excisional B Incisiconal B ned iopsy Biopsy
recurren Lt.conjunc and tars mass 0.8 Figure ( Lt +Rt Bilater Limbal conjunctiva mass nt ctivl sal 0.8 3): The sit Rt . Limbal conjunctival mass ral al 6.2 te of the le lt . Limbal conjunctival mass 3.8 Site of the esions in t Lt Limbal conjunctival mass 3.1 e lesions the study Rt. c t . conjunctivl mass 3 27 undet s conjunctivl mass 27 30.8 termined site 7.7 Percent
Table (2): The Diagnosis of All lesions in the study:- Percent Frequency The diagnosis 10.8 14 scc 6.9 9 carcinoma in situ .8 1 Melanoma .8 1
Non Hodgkin 's lymphoma
.8 1
High grade Malignant tumour
.8 1
basal cell carcinoma
4.6 6 CIN-severe dysplasia 5.4 7 CIN-moderate dysplasia .8 1 CIN-mild dysplasia 3.1 4
pterygium with CIN \ moderate dysplasia 13.1 17 pterygium 10.0 13 pinguecula 1.5 2 pterygium or pinguecula 2.3 3 Junctional nevus 4.6 6 compound nevus .8 1
compound nevus CIN/ sever dysplasia
.8 1
compound nevus with cyst formation.
.8 1 subepithelial nevus 1.5 2 Hemangioma 6.2 8 pyogenic granuloma .8 1 cavernous haemangioma 2.3 3 squamous papilloma 2.3 3 Dermoid cyst 1.5 2 Benign cyst 1.5 2 granulomatous conjunctivitis 5.4 7
Active chronic conjunctivitis
4.6 6 chronic conjunctivitis 1.5 2 Acute conjunctivitis 1.5 2
Inflammed granulation tissue
1.5 2 chalazion .8 1 pilar cyst 100.0 130 Total
| Fig lesi gure (4): T ions in the ne The diagno e study:- eoplastic lesio 58% osis divide on
ed into neooplastic an n nd non neo non neoplastic lesion 42% oplastic c
Table (3): Frequency of neoplastic lesions in the study:-(n=76) Percent Frequency neoplastic lesion 23.7 18 Malignant Tumors 34.2 26 CIN 42.1 32 Benign lesions 100.0 76 Total
Table (4): Frequency of Malignant Tumors:-(n=18) Percent Frequency Malignant Tumors 27.8 5 scc/well differentiated 16.7 3 scc/moderate differentiated 22.2 4 scc/poorly differentiated 5.6 1 basaliod scc 5.6 1 Acatholytic scc 5.6 1 Melanoma 5.6 1
Non Hodgkin 's lymphoma
5.6 1
basal cell carcinoma
5.6 1
High grade Malignant tumour
100.0 18
Table(5): Malignant Tumors versus Sex Cross tabulation Total female Male Malignant Tumors 5 2 3 scc/well differentiated 3 0 3 scc/moderte differentiated 4 3 1 scc/poorly differentiated 1 0 1 basaliod scc 1 0 1 Acatholytic scc 1 0 1 Melanoma 1 0 1 Non Hodgkin 's lymphoma
1 0
1 basal cell carcinoma
1 0
1 High grade Malignant tumour
18 5
13 Total
Table (6): Malignant Tumors versus Age Cross tabulation total <10 10-19 20-29 30-39 40-49 50-59 60-69 >70 Malignant Tumors 5 0 0 1 2 1 1 0 0 scc/well differentiated 3 0 0 0 0 2 0 1 0 scc/moderate differentiated 4 1 0 0 0 0 0 3 0 scc/poorly differentiated 1 0 0 0 0 0 0 0 1 basaliod scc 1 0 0 0 0 0 0 0 1 Acatholy lic scc 1 0 1 0 0 0 0 0 0 Melanoma 1 1 0 0 0 0 0 0 0 Non Hodgkin 's lymphoma 1 0 0 0 0 0 0 0 1 basal cell carcinoma
1 0 0 0 0 0 0 0 1 High grade Malignant
tumour 18 2 1 1 2 3 1 4 4 Total
Table (7): Frequency of Benign lesions:-(n=32) Percent Frequency Benign lesion 9.4 3 junctional nevus 18.8 6 compound nevus 3.1 1
compound nevus CIN/ severe dysplasia
3.1 1
compound nevus with cyst formation..
3.1 1
sub epithelial nevus
6.3 2 Hemangioma 25.0 8 pyogenic granuloma 3.1 1 cavernous haemangioma 9.4 3 squamous papilloma 9.4 3 Dermoid cyst 6.3 2 Benign cyst 3.1 1 pilar cyst 100.0 32 Total
Table (8): Benign lesions versus AGE Cross tabulation Total AGE Benign lesions <10 10-19 20-29 30-39 40-49 50-59 60-69 >70 3 1 1 0 1 0 0 0 0 junctional nevus 6 3 3 0 0 0 0 0 0 compound nevus 1 0 0 1 0 0 0 0 0 compound nevus CIN/ severe dysplasia 1 0 0 0 0 1 0 0 0 compound nevus
with cyst formation.
1 0 1 0 0 0 0 0 0 sub epithelial nevus
2 0 0 0 0 0 1 0 1 Hemangioma 8 2 1 3 1 0 0 1 0 pyogenic granuloma 1 0 0 0 0 0 1 0 0 cavernous haemangioma 3 0 1 1 0 1 0 0 0 squamous papilloma 3 0 0 3 0 0 0 0 0 Dermoid cyst 2 1 0 0 0 0 0 0 1 Benign cyst 1 0 0 0 0 0 1 0 0 pilar cyst 32 7 7 8 2 2 3 1 2 Total
